摘要
目的探讨组蛋白去乙酰化酶抑制剂伏立诺他（suberoylanilide hydroxamic acid，SAHA）对糖尿病大鼠肾小管间质纤维化的作用及其可能机制。方法SD大鼠分为3组：对照组（Con）、糖尿病（diabetes mellitus，DM）组及SAHA治疗组，每组9只。以链脲菌素（streptozotocin，STZ）诱导糖尿病，于成模第9周治疗组给予剂量为25mg·kg-1·d-1的SAHA灌胃。16周末处死大鼠，检测相应生化指标，观察肾组织病理改变，免疫组化及Western印迹检测肾组织转化生长因子β1（transforming growth factor-β1，TGF-β1）、Smad2、Smad3、Smad7、胶原蛋白I（collagen Ⅰ，Col—Ⅰ）和胶原蛋白Ⅲ（collagen Ⅲ，Col-Ⅲ）的定位及蛋白表达。结果与Con组相比，DM组大鼠血糖、尿微量白蛋白／尿肌酐之比值（urinary trace albumin／urinary creatinine，ACR）、三酰甘油（triglyceride，TG）、总胆固醇（total cholesterol，TC）增加，肾小管间质纤维化病变增加，肾组织中Smad7蛋白减少，TGF-β1、磷酸化（p）-Smad2和p-Smad3蛋白增多，Col-Ⅰ和Col-Ⅲ蛋白在间质沉积增多，差异均有统计学意义（均P〈0．05）。与DM组比较，SAHA治疗组ACR降低，肾小管间质的纤维化病变减轻，Smad7蛋白表达增加，TGF-β1、P-Smad2和p-Smad3蛋白表达减少，Col-Ⅰ和Col-Ⅲ蛋白在间质的沉积减少，差异均有统计学意义（均P〈0．05）。结论SAHA可能通过提高Smad7蛋白水平，恢复TGF-β1信号通路的适度转导，进而减轻糖尿病大鼠肾小管间质纤维化病变。
Objective To explore the effects and possible mechanism of histone deacetylase inhibitor SAHA on the interstitial fibrosis induced by diabetes. Methods The SD rats were divided into three groups： control group （Con, n=9）, diabetes mellitus （DM） group （n=9） and SAHA treatment group （n=9）. The diabetic rat model was established by injecting streptozotocin （STZ） through tail vein. After 8 weeks, the SAHA treatment group rats were fed with a SAHA solution （25 mg·kg-1·d-1） by gastric garage. After 16 weeks, all rats were sacrificed to detect relevant biochemical parameters, and observe the changes of pathomorphology in kidney. In addition, immunohistochemistry staining and Western blotting were employed to detect the protein expressions of transforming growth factor- β1 （TGF-β1）, Smad2, Smad3, p-Smad2, p-Smad3, Smad7, collagen-Ⅰ and collagen-Ⅲ, respectively. Results Compared with Con group, the levels of blood glucose （BG）, urinary trace albumirdurinary creatinine （ACR）, triglyceride （TG） and total cholesterol （TC） in the diabetic group were all increased significantly （all P 〈 0.05）, the protein expressions of TGF-131, p-Smad2, p-Smad3, collagen- Ⅱ and collagen-Ⅲ in kidney were all increased in diabetic group （all P 〈 0.05）, and the expression of Smad7 was significantly reduced （P 〈 0.05）. Compared with DM group, the levels of ACR was reduced, the renal fibrosis was alleviated, the protein expressions of TGF-β1, p-Smad2, p-Smad3, collagen- I and collagen- III in SAHA group were all decreased （all P 〈 0.05）, and the expression of Smad7 was increased significantly （P 〈 0.05）. Conclusion SAHA may restore the protein level of Smad7 by enhancing protein stability, then promote the moderate transduction of TGF- β1/Smads signaling pathway, which reduce the fibrosis of renal tubules in diabetic rats.
出处
《中华肾脏病杂志》
CSCD
北大核心
2017年第12期929-934,共6页
Chinese Journal of Nephrology
基金
国家自然科学基金（81541102）
贵州省科技厅联合基金（黔科合LH字[2015]7335）
贵阳市科技局基金（筑科合同[20151001]社14号）
贵阳医学院博士启动基金（院博合J字[2014]008）
关键词
糖尿病肾病
纤维化
SMAD7
伏立诺他
Diabetic nephropathies
Fibrosis
Smad7
Suberoylanilide hydroxamic acid
